Claims for Patent: 7,790,743

Summary for Patent: 7,790,743

Title:	Modulators of cellular adhesion
Abstract:	The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof; wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof; and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
Inventor(s):	Wang Shen, Kenneth Barr, Johan D. Oslob, Min Zhong
Assignee:	Bausch and Lomb Ireland Ltd
Application Number:	US11/934,049
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,790,743
Patent Claims:	1. A method of treating an immune or inflammatory disorder mediated through an interaction of a CD11a/CD18 leukointegrin with a member of the ICAM family of cellular adhesion molecules in a subject, comprising administering to said subject a therapeutically effective amount of a compound that is a competitive inhibitor of said interaction, wherein said compound has a structure of Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an amino acid side chain, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, SO2—NHC(═O)R1B , —OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1C R1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I; R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1 wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHRi; D is N; wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O) NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1; L is C═O; further wherein the disorder is selected from the group consisting of psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, dermatitis, meningitis, uveitis, eczema, asthma, poison ivy, poison oak, rheumatoid arthritis, Sjorgen's syndrome, and pulmonary fibrosis; and whereby intercellular leukocyte adhesion is reduced. 2. The method of claim 1 further comprising administering to said subject a therapeutically effective amount of a compound that is a competitive inhibitor of an interaction of a CD11b/CD18 leukointegrin with a member of the ICAM family of cellular adhesion molecules. 3. The method of claim 1 wherein said disorder is mediated by lymphocytes. 4. The method of claim 1 wherein said disorder is mediated by non-lymphocyte leukocytes. 5. The method of claim 1 wherein said immune or inflammatory disorder is a chronic disorder. 6. The method of claim 1 wherein said inflammatory disorder is selected from the group consisting of adult respiratory distress syndrome, asthma, and pulmonary fibrosis. 7. The method of claim 1 wherein said inflammatory disorder is selected from the group consisting of psoriasis, dermatitis, eczema, asthma, uveitis, rheumatoid arthritis, Sjorgen's syndrome, inflammatory bowel disease, poison ivy, and poison oak. 8. The method of claim 7 wherein said inflammatory disorder is an eye disease selected from the group consisting of uveitis and Sjorgen's syndrome. 9. The method of claim 7 wherein said inflammatory disorder is selected from the group consisting of psoriasis, dermatitis, eczema, poison ivy, and poison oak. 10. The method of claim 7 wherein said inflammatory bowel disease is Crohn's disease or ulcerative colitis. 11. The method of claim 1 wherein said immune disorder is selected from the group consisting of psoriasis, uveitis, rheumatoid arthritis and Sjorgen's syndrome. 12. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an amino acid side chain, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O) N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, SO2—NHC(═O)R1B,—OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1C R1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I; R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1 wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHRi; D is N; wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1; L is C═O; and wherein said disease is selected from the group consisting of adult respiratory distress syndrome, psoriasis, inflammatory bowel disease, dermatitis, uveitis, eczema, asthma, poison ivy, poison oak, Sjorgen's syndrome, and pulmonary fibrosis. 13. A method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof, wherein; R1 and R2 are each independently hydrogen, an amino acid side chain, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B) 2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, SO2—NHC(═O)R1B, —OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1C R1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I; R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1 wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHRi; D is N; wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O) NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1, L is C═O; and wherein said disease is rheumatoid arthritis. 14. The method of claim 1, 12 or 13 wherein said administration is systemic or local and is performed via an oral, topical, intraperitoneal, intravenous injection, depot injection, subcutaneous injection, nasal, intramuscular injection, rectal, vaginal, transdermal, or an ocular route. 15. The method of claim 1, 12 or 13 wherein said compound is administered in a formulation comprising an excipient. 16. The method of claim 15 wherein said excipient is a penetration enhancing agent. 17. The method of claim 15 wherein said formulation is a spray, a liquid, a polymeric microencapsulated matrix, an ointment, a cream, a lotion, a solid, a suppository, a drop, or a powder. 18. The method of claim 1, 12 or 13 further comprising administering a second therapeutic agent selected from the group consisting of an antiinflammatory agent, a palliative agent, and a therapeutic agent which treats disorders mediated by a CD11a/CD18 or CD11b/CD18 leukointegrin. 19. A method of inhibiting an interaction between a CD11a/CD18 leukointegrin and a member of the ICAM family of cellular adhesion molecules comprising administering to a cell an effective amount of a compound that is a competitive inhibitor of said CD11/CD18-ICAM interaction whereby said ligand/receptor interaction between said integrin and said intercellular adhesion molecule is decreased, and wherein said compound comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently hydrogen, an amino acid side chain, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—RIE)—O—, —C(═N—RIE)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, SO2—NHC(═O)R1B ,—OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1C R1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I; R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1 wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHRi; D is N; wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O) NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1; and, L is C═O. 20. The method of claim 19 further comprising administering to said cell a therapeutically effective amount of a compound that is a competitive inhibitor of an interaction between a CD11b/CD18 leukointegrin and a member of the ICAM family of cellular adhesion molecules. 21. The method of claim 1, 19, 12, or 13 wherein the compound of Formula I is a compound wherein n is 2 and R4 for each occurrence, is independently halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1. 22. The method of claim 1, 19, 12, or 13 wherein the compound of Formula I is a compound having the following formula: wherein R4A and R4B are independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1; and RB1, RB2 and RE are independently hydrogen or substituted or unsubstituted C1-6 alkyl. 23. The method of claim 22 wherein R4A and R4B are independently halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1. 24. The method of claim 23 wherein the compound of Formula I is a compound wherein R4A and R4B are independently a halogen which is F, Cl, Br or I. 25. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein R3 is carboxyl, protected carboxyl or a prodrug thereof, wherein R3 is C(═O)R3A, wherein R3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures: 26. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and Rs is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety. 27. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein R1A is Ar2, —OR1B, —SR1B or —NR1BR1C; or an alkyl or heteroalkyl moiety; and Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or R1B and R1C, taken together with the nitrogen atom to which they are attached, form a heterocylic or heteroaryl moiety. 28. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen, C1-6alkyl, C2-6alkenyl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety. 29. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein t is 1-3; and RP3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 30. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 is a moiety having one of the following structures: wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R2C is hydrogen, CN, —C═NMe, ═NO2, ═NC(═O)NH2, ═NS(O)2R, or ═NS(O)2NRR′; wherein R and R′ are each independently hydrogen or methyl; R2D is Ar2, hydrogen, halogen, CN, NO2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R2E and R2F, taken together, form a substituted or unsubstituted heterocyclic or heteroaryl moiety. 31. The method of claim 30, wherein the compound of Formula I is a compound wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form a moiety having one of the following structures: wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2 , taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 32. The method of claim 31, wherein the compound of Formula I is a compound wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form a moiety having one of the following structures: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3, or —N(CH3)2. 33. The method of claim 32, wherein the compound of Formula I is a compound wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form a moiety having one of the following structures: 34. The method of claim 30, wherein the compound of Formula I is a compound wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D has the following structure: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3 or —N(CH3)2; R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; and q is 1 or 2. 35. The method of claim 30, wherein the compound of Formula I is a compound wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D has one of the following structures: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3 or —N(CH3)2; R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; q is 1 or 2; and R2C is lower alkyl. 36. The method of claim 26, wherein the compound of Formula I is a compound wherein R3A is independently hydrogen, lower alkyl, phenyl or benzyl. 37. The method of claim 26, wherein the compound of Formula I is a compound wherein Rs is hydrogen. 38. The method of claim 26, wherein the compound of Formula I is a compound wherein Ar2 has one of the following structures: wherein s is an integer from 0-2; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —ORG1, —S RG1, —NRG1RG2—, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently lower alkyl, or when Y is O RP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; RP3 is lower alkyl or —N(RP2)2; and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety. 39. The method of claim 26, wherein the compound of Formula I is a compound wherein Ar2 has one of the following structures: 40. The method of claim 27, wherein the compound of Formula I is a compound wherein R1A has one of the following structures: wherein s is an integer between 0 and 2; each occurrence of RP1 is independently lower alkyl or is —GRG1 wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower alkyl, aryl or heteroaryl. 41. The method of claim 40, wherein the compound of Formula I is a compound wherein R1A has one of the following structures: wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen or lower alkyl. 42. The method of claim 28, wherein the compound of Formula I is a compound wherein —N(R2AAr2, has one of the following structures: wherein X1 is N or CRP1; s is an integer from 0-5; and each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and RP3 is alkyl, heteroalkyl, aryl or heteroaryl. 43. The method of claim 26, wherein the compound of Formula I is a compound wherein —C(═O)NHC(R1)(R2)R3 has the structure —C(═O)NHC(—C(Rs)Ar2)CO2R3A wherein R3A and Rs, taken together, form a substituted or unsubstituted heterocyclic moiety. 44. The method of claim 43 wherein the compound of Formula I is a compound wherein —C(═O)NHC(—C(Rs)Ar2)CO2R3A has one of the following structures: wherein Ar2 is heterocycle, aryl or heteroaryl; and X1 is O, S or NH. 45. The method of claim 44, wherein the compound of Formula I is a compound wherein —C(═O)NHC(—C(Rs)Ar2)CO2R3A has one of the following structures: wherein X1 is O, S or NH; and X2 is N or CH. 46. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein AR1 has one of the following structures: wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 is independently N or CRQ1; X5 is O, S or NRQ2; AR3 is a heterocyclic, aryl or heteroaryl moiety; each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3R Q4, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group. 47. The method of claim 46, wherein the compound of Formula I is a compound wherein AR1 has one of the following structures: wherein X0 is F or Cl; X2 is N or CRQ1; X5 is CH, O, S or NH; RQ1 is hydrogen, methyl, —CF3, —OCH3, —OCF3 or halogen. 48. The method of claim 47, wherein the compound of Formula I is a compound wherein AR1 has one of the following structures: 49. The method of claim 48, wherein the compound of Formula I is a compound wherein AR1 has one of the following structures: 50. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein AR1—L— has one of the following structures: 51. The method of claim 50, wherein the compound of Formula I is a compound wherein AR1—L— has one of the following structures: 52. The method of claim 1, 19, 12, or 13, wherein the compound of Formula I is a compound wherein AR1—L— is a moiety having one of the following structures: and —C(═O)NHC(R1)(R2)R3 is a moiety having one of the following structures: wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R3A is hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety; and R2D is a moiety having one of the following structures: wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; and wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 53. The method of claim 52 wherein the compound of Formula I is a compound wherein R2A and R3A are each hydrogen. 54. The method of claim 52 wherein the compound of Formula I is a compound wherein R2D is a moiety having one of the following structures: 55. The method of claim 1, 19, 12, or 13 wherein the compound is: 56. The method of claim 1, 19, 12, or 13 wherein the compound is: 57. The method of claim 1, 19, 12, or 13 wherein the compound is: 58. The method of claim 1, 19, 12, or 13 wherein the compound is: 59. The method of claim 1, 19, 12, or 13 wherein the compound is: 60. The method of claim 1, 19, 12, or 13 wherein the compound is: 61. The method of claim 1, 19, 12, or 13 wherein the compound is: 62. The method of claim 1, 19, 12, or 13 wherein the compound is: 63. The method of claim 1, 19, 12, or 13 wherein the compound has one of the following structures: 64. The method of claim 1, 19, 12, or 13 wherein the compound has one of the following structures: 65. The method of claim 1, 19, 12, or 13 wherein the compound has one of the following structures: 66. The method of claim 1, 19, 12, or 13 wherein the compound has one of the following structures: 67. The method of claim 1, 19, 12, or 13 wherein the compound has one of the following structures: 68. The method of claim 1, 19, 12, or 13 wherein the compound having a structure of Formula I is the compound wherein: AR1 is: —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: R3A is hydrogen; Rs is hydrogen; Ar2 is: s is an integer of 1 or 2; each occurrence of RPI is independently hydrogen, halogen, or —GRG1, wherein G is —SO2—, or —SO2NRG2—; and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety. 69. The method of claim 68 wherein s is an integer of 2, each occurrence of RP1 is independently hydrogen, halogen, or —GRG1, G is —SO2—, and RG1 is methyl.